This invention relates generally to methods and materials for the treatment of cancer. More specifically, the invention relates to methods and materials for enhancing the effectiveness of cancer therapies.
Conventional treatment for cancers involves the use of chemotherapeutic agents, radiation, and surgery, either alone or in combination. The medical arts have developed a number of treatments based upon the foregoing therapies. The present invention is directed to specific materials which can act to enhance the effectiveness of the foregoing therapies.
Galectins comprise a family of proteins which are expressed by plant and animal cells and which bind xcex2-galactoside sugars. These proteins can be found on cell surfaces, in cytoplasm, and in extracellular fluids. They have a molecular weight in the general range of 29-34 kD; they have an affinity for xcex2-galactoside containing materials, and have been found to play a number of important roles in biological processes including cell migration, cell-cell adhesion, angiogenesis, cell fusion and other cell-cell interactions, as well as immune-based reactions and apoptosis. As such, the role of galectins is very strongly tied to cancer and other proliferative diseases. While there are a large number of galectins which manifest the foregoing activities, galectin-3 and galectin-1 have been strongly implicated in connection with cellular processes involving cancers.
Galectin-3 is a carbohydrate binding protein having a molecular weight of approximately 30,000. It is composed of two distinct structural motifs, an amino-terminal portion containing Gly-X-Y tandem repeats which are characteristic of collagens, and a carboxyl-terminal portion containing a carbohydrate binding site. Galectin-3 is found in almost all tumors, and has a binding affinity for xcex2-galactoside-containing glyco-conjugates. Galectin-3 is believed to play a role in mediating cell-cell interactions and thereby fostering metastasis. It has been found that cells which have high expressions of galectin-3 are more prone to metastasis and are more resistant to apoptosis induced by chemotherapy or radiation. It has also been reported in the literature that galectin-3 plays a role in promoting angiogenesis.
Galectin-1 is a highly conserved homodimer of 14-15 kD and is one of the most abundant of the galectins. It binds to laminin which has been found to exert strong regulatory effects on cellular interactions such as adhesion, proliferation, migration and differentiation. In this regard, galectin-1 has been found to strongly influence these processes in various cells. It is believed to be implicated in the secretion of a number of cellular growth factors and interleukins. Galectin-1 has been found to be expressed at very high levels in many cancer cells and is strongly implicated in metastasis.
In accord with the present invention, it has been found that certain therapeutic materials can bind to galectins thereby inactivating them toward interaction with other carbohydrate materials and/or cells. Specifically, it has been found that treatment of galectin bearing cells with the therapeutic materials of this invention can inhibit the interaction of those cells with other cells and/or biomolecules and thereby inhibit angiogenesis and enhance the efficacy of apoptosis-inducing therapies such as chemotherapy or radiation. Furthermore, these materials can inhibit cell-cell interactions and thereby enhance the effectiveness of surgical therapies by inhibiting metastases, which are often initiated by surgical dislodgement of cells.
As will be explained in detail hereinbelow, the materials of the present invention are generally comprised of natural or synthetic polymers and oligomers. They are very low in toxicity and interact synergistically with heretofore employed cancer therapies so as to increase the effectiveness thereof. Through the use of the present invention, the dosages of potentially toxic therapies such as chemotherapies and radiation may be reduced. Likewise, the effectiveness of surgical therapies is enhanced by the use of the present invention. For example, since the methodology of the present invention acts to inhibit the post-surgery metastatic process, use of this invention allows a surgeon to implement more aggressive surgical therapies without being limited by the possibility of precipitating metastatic events. These and other advantages of the invention will be discussed hereinbelow.
There is disclosed herein a method for enhancing the efficacy of a therapeutic treatment for cancer in a patient. The treatment being enhanced may comprise chemotherapy, radiation therapy, surgery and combinations thereof. The method of the present invention comprises administering to a patient a therapeutically effective amount of a compound which binds to a galectin. This compound may be administered prior to, after, or concomitant with the other treatment.
A preferred class of therapeutic materials of the present invention comprises a polymeric backbone having side chains dependent therefrom. The side chains are terminated by a galactose or arabinose unit. This material may be synthetic, natural, or semi-synthetic. In one particular embodiment, the therapeutic compound comprises a substantially demethoxylated polygalacturonic acid backbone which is interrupted with rhamnose residues.
In general, the materials of the present invention have a molecular weight in excess of 300 dalton. One specific group of materials has a molecular weight in the range of 300 to 2,000 daltons. In those instances where the materials of the present invention are based upon complex carbohydrates such as pectins, a preferred group of materials has a molecular weight in the range of 1-50 kilodalton. The therapeutic materials of the present invention may be administered orally, by injection, transdermally, or by topical application, depending upon the specific type of cancer being treated, and the adjunct therapy.